Peter Karl Sorger Explained

Peter Karl Sorger
Birth Place:Halifax Nova Scotia, Canada
Otto Krayer Professor of Systems Pharmacology, Harvard Medical School
Spouse:Caroline Shamu
Thesis Title:The transcriptional regulation of heat shock genes
Thesis Year:1988
Doctoral Advisor:Hugh Pelham

Peter Karl Sorger (born February 13, 1961, in Halifax Nova Scotia, Canada) is a systems and cancer biologist and Otto Krayer Professor of Systems Pharmacology in the Department of Systems Biology at Harvard Medical School.[1] Sorger is the founding head of the Harvard Program in Therapeutic Science (HiTS), director of its Laboratory of Systems Pharmacology (LSP), and co-director of the Harvard MIT Center for Regulatory Science. He was previously a Professor of Biology and Biological Engineering at the Massachusetts Institute of Technology where he co-founded its program on Computational and Systems Biology (CSBi). Sorger is known for his work in the field of systems biology and for having helped launch the field of computational and systems pharmacology. His research focuses on the molecular origins of cancer and approaches to accelerate the development of new medicines. Sorger teaches Principles and Practice of Drug Development at Massachusetts Institute of Technology and Harvard University.

Early life

Sorger was born on February 13, 1961, in Halifax Nova Scotia, Canada to Scottish and Austrian parents. His family immigrated to the US in 1963. He graduated summa cum laude from Harvard College in 1983 (in Biochemistry) where he studied the assembly of icosahedral viruses under the supervision of Stephen C. Harrison. He received his PhD for Biochemistry as a Marshall Scholar from Trinity College, Cambridge for research on the transcriptional regulation of heat shock genes[2] [3] under the supervision of Hugh Pelham at the Medical Research Council Laboratory of Molecular Biology in Cambridge, England. He then trained as a Richard Childs Fellow and Lucille P. Markey Scholar with Harold Varmus and Andrew Murray at the University of California, San Francisco.

Career

Sorger joined the MIT Department of Biology in 1994 following a year as a visiting scientist with Anthony A. Hyman at the European Molecular Biology Laboratory, Heidelberg, Germany. Sorger became a full Professor in the MIT Biology and Biological Engineering Departments in 2004.

Sorger's postdoctoral and early faculty research led to the first reconstitution of a chromosome-microtubule attachment (a yeast kinetochore) and the subsequent identification of multiple kinetochore proteins.[4] [5] His group identified mammalian homologs of the checkpoint proteins that regulate entry into mitosis, and showed that mutations in these genes can be oncogenic because they cause chromosome instability.[6] [7] [8] This work contributed to the understanding of the faithful transmission of chromosomes from mother to daughter cells. Defects in these mechanisms cause aneuploidy that plays a major role in oncogenic transformation.

Working closely with Doug Lauffenburger and funded by the Defense Advanced Research Projects Agency and the National Institutes of Health's National Centers for Systems Biology program,[9] Sorger's work in the 1990s increasingly focused on oncogenesis itself and on mammalian signal transduction.[10] Sorger and Lauffenburger's approach combined molecular genetics, live-cell microscopy and mechanistic computational modeling.[11] [12] Their focus on biochemistry REF was unusual in an era dominated by genomics and ultimately led Sorger to co-found the software company Glencoe Software and the biotech company Merrimack Pharmaceuticals.[13] Subsequent work by Sorger' group led to a new understanding of stochastic fluctuation in cellular responses to natural ligands and drugs[14] [15] and to the development of a range of innovative computational methods, including the biochemistry-specific Python PySB[16] and the natural language processing and knowledge assembly system INDRA.[17] [18]

In 2011, Sorger was active in the development of the discipline of Quantitative Systems Pharmacology, including overseeing the preparation of a widely cited white paper for the NIH entitled "Quantitative and Systems Pharmacology in the Post-genomic Era: New Approaches to Discovering Drugs and Understanding Therapeutic Mechanisms".[19] This white paper envisioned the emergence of an empirically based but computationally sophisticated approach to the science underlying development of innovative new medicines. Sorger moved to Harvard Medical School[20] to pursue these approaches by establishing the Laboratory of Systems Pharmacology, which merges laboratory experiments, computer science, and medicine to fundamentally improve drug discovery.[21] Funding from the Massachusetts Life Sciences Center in 2014[22] and 2017[23] [24] made the lab a reality and it now has 150 faculty trainees and staff from Boston-area institutions including Harvard University, MIT, Tufts University, Northeastern University and Harvard-affiliated Hospitals.

Sorger's research involves multiple systems pharmacology approaches to cancer. The first focuses on preclinical pharmacology, the stage at which the molecular mechanisms of disease are studied and new drugs sought. An investigation into the causes of irreproducibility drug-response measurements[25] led to a series of conceptual,[26] computational,[27] and experimental improvements[28] in scoring drug action that are now widely used in academe and industry and have enabled the discovery of new mechanisms of action for existing drugs.[29] Recent work has focused on deep learning as means to further understand complex protein networks and drug mechanisms.[30] [31] The second project involves developing methods to study drug mechanism at scale in patients through highly multiplexed tissue imaging[32] [33] of the biopsies routinely acquired from patients (particularly cancer patients).[34] This has led to a very rapidly growing tissue imaging and digital histology program[35] that is part of the US National Cancer Institute Moonshot and promises to substantially advance precision cancer care.[36] The third project involves studying the clinical trial record to understand how successful and failed trials differ. An early success was the discovery that the great majority of approved combination cancer therapies exhibit independent action – not synergy.[37] [38] As Merck & Co. investigators subsequently realized, this fundamentally changes how immunotherapy combinations should be developed.[39] The group is now engaged in a large-scale effort[40] to digitize and make freely available all survival data from Phase 3 clinical trials.[41]

COVID-19 pandemic research

To address the need for face masks, respirators and other personal protective equipment for healthcare workers in the early COVID-19 pandemic, Sorger, physician Nicole LeBoeuf and MD-PhD student Deborah Plana established the Boston Area Pandemic Fabrication team (PanFab).[42] [43] This team of students and alumni from MIT and Harvard teamed up with local industry and led a series of 3D printing and rapid-turn manufacturing projects to make face shields,[44] mask frames,[45] powered air purifying respirators[46] and new ways to sterilize and reuse 95 respirators.[47] PanFab led to over a dozen open access publications and designs, including a thorough review of lessons learned[48] and a hope that we can be better prepared for future pandemics.

Notes and References

  1. Web site: Peter Sorger . sysbio.med.harvard.edu . 18 December 2021 . en.
  2. Sorger. P. K.. Pelham. H. R.. 9 September 1988. Yeast heat shock factor is an essential DNA-binding protein that exhibits temperature-dependent phosphorylation.. Cell. 24. 6. 855–864. 10.1016/S0092-8674(88)91219-6. 3044613. 45178990. 29 November 2021.
  3. Sorger. P. K.. Lewis. M. J.. Pelham. H. R.. September 3, 1987. Heat shock factor is regulated differently in yeast and HeLa cells. Nature. 329. 6134. 81–84. 10.1038/329081a0. 3306402. 1987Natur.329...81S. 4315665. 29 November 2021.
  4. He . X.. Rines . D. R.. Espelin . C. W.. Sorger . P. K.. 2001. Molecular analysis of kinetochore-microtubule attachment in budding yeast. Cell. 106. 2. 195–206. 10.1016/S0092-8674(01)00438-X. 11511347. 15917728. free.
  5. Kaplan. K. B.. Hyman. A. A.. Sorger. P. K.. 1997. Regulating the yeast kinetochore by ubiquitin-dependent degradation and Skp1p-mediated phosphorylation. Cell. 91. 4. 491–500. 10.1016/s0092-8674(00)80435-3. 9390558. 9159412. free.
  6. Foijer . F.. Albacker . L. A.. Bakker . B.. Spierings . D.C.. Yue . Y.. Xie . S. Z.. Davis . S.. Lutum-Jehle . A.. Takemoto . D.. 2017. Deletion of the MAD2L1 spindle assembly checkpoint gene is tolerated in mouse models of acute T-cell lymphoma and hepatocellular carcinoma. eLife. 6 . e20873. 10.7554/eLife.20873. 28318489. 5400506. free.
  7. Dobles . M.. Liberal . V.. Scott . M. L.. Benezra . R.. Sorger . P. K.. 2000. Chromosome missegregation and apoptosis in mice lacking the mitotic checkpoint protein Mad2 . Cell. 101 . 6 . P635-645. 10.1016/S0092-8674(00)80875-2. 10892650. 12738892. free.
  8. Michel . L. S.. Liberal . V.. Chatterjee . A.. Kirchwegger . R.. Pasche . B.. Gerald . W.. Dobles . M.. Sorger . P. K.. Murty . V. V. V. S.. Benzra . R.. MAD2 haplo-insufficiency causes premature anaphase and chromosome instability in mammalian cells. Nature. 2001. 409 . 6818 . 355–359. 10.1038/35053094. 11201745. 4417961. 16 December 2021.
  9. Web site: NIH grant aids MIT systems biology. MIT News. 15 September 2003. 17 December 2021.
  10. Janes. K. A.. Albeck. J. G.. Gaudet. S.. Sorger. P. K.. Lauffenburger. D. A.. Yaffe. M. B.. 2005-12-09. A systems model of signaling identifies a molecular basis set for cytokine-induced apoptosis. Science. 310. 5754. 1646–53. 16339439. 10.1126/science.1116598. 2005Sci...310.1646J. 22495219. 16 December 2021.
  11. Janes. K. A.. Gaudet. S.. Albeck. J. G.. Nielsen. U. B.. Lauffenburger. D. A.. Sorger. P. K.. 2006-03-24. The response of human epithelial cells to TNF involves an inducible autocrine cascade. Cell. 124. 6. 1225–1239. 10.1016/j.cell.2006.01.041. 16564013. 540286. free.
  12. Albeck. J. G.. Burke. J. M.. Spencer. S. L.. Lauffenburger. D. A.. Sorger. P. K.. 2008-12-02. Modeling a Snap-Action, Variable-Delay Switch Controlling Extrinsic Cell Death. PLOS Biology. 6. 12. 2831–2852. 2592357. 10.1371/journal.pbio.0060299. 19053173. free.
  13. News: Friendster for Proteins. 17 December 2021. Forbes. Feb 23, 2007.
  14. Spencer. S. L.. Gaudet. S.. Albeck. J. G.. Burke. J. M.. Sorger. P. K.. 2009-05-21. Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis. 2858974. 10.1038/nature08012. Nature. 459. 7245. 428–32. 19363473. 2009Natur.459..428S.
  15. Spencer. S. L.. Sorger. P. K.. 2011-03-18. Measuring and modeling apoptosis in single cells. 3087303. 10.1016/j.cell.2011.03.002. Cell. 144. 6. 926–39. 21414484.
  16. Lopez. C. F.. Muhlich. J. L.. Bachman. J. A.. Sorger. P. K.. 2013-02-19. Programming biological models in Python using PySB. Molecular Systems Biology. 9. 646. 10.1038/msb.2013.1. 3588907. 23423320.
  17. Prabhakar . Arati. The merging of humans and machines is happening now. WIRED. 17 December 2021.
  18. 10.15252/msb.20177651. 13. 11. 954. Gyori. B. M.. Bachman. J. A.. Subramanian. K.. Muhlich. J. L.. Galescu. L.. Sorger. P. K.. From word models to executable models of signaling networks using automated assembly. Molecular Systems Biology. 2017-11-24. 29175850. 5731347.
  19. Sorger . P. K.. Allerheiligen . S.R.B.. Quantitative and Systems Pharmacology in the Post-genomic Era: New Approaches to Discovering Drugs and Understanding Therapeutic Mechanisms. An NIH White Paper by the QSP Workshop Group. October 2011. 1–47.
  20. Web site: Xie . K.. Systematic Drug Discovery. Harvard Magazine. 17 June 2013. 17 December 2021.
  21. News: Bebinger . M.. State-Funded Lab At Harvard Medical Aims To Reinvent Drug Discovery. 17 December 2021. WBUR. August 10, 2015.
  22. Web site: Harvard Medical School Opens Laboratory of Systems Pharmacology. Massachusetts Life Sciences Center. 24 September 2014. 17 December 2021.
  23. Web site: Investing in Innovation: Massachusetts Life Sciences Center gives Boston biomedicine an $18 million boost. HMS News. 19 May 2017. 17 December 2021.
  24. Web site: HARVARD MEDICAL SCHOOL LABORATORY OF SYSTEMS PHARMACOLOGY. BDS Architects. 17 December 2021.
  25. 10.1016/j.cels.2019.06.005. 9. 1. 35–48.e5. Niepel. M.. Hafner. M.. Mills. C. E.. Subramanian. K.. Williams. E. H.. Chung. M.. Gaudio. B.. Barrette. A. M.. Stern. A. D.. Hu. B.. Korkola. J. E.. LINCS Consortium. Gray. J. W.. Birtwistle. M. R.. Heiser. L. M.. Sorger. P. K.. A Multi-center Study on the Reproducibility of Drug-Response Assays in Mammalian Cell Lines. Cell Systems. 2019-07-05. 31302153. 6700527.
  26. 10.1038/nchembio.1337. 9. 11. 708–14. Fallahi-Sichani. M.. Honarnejad. S.. Heiser. L. M.. Gray. J. W.. Sorger. P. K.. Metrics other than potency reveal systematic variation in responses to cancer drugs. Nature Chemical Biology. 2013-11-01. 24013279. 3947796.
  27. 10.1038/nmeth.3853. 13. 6. 521–527. Hafner. M.. Niepel. M.. Chung. M.. Sorger. P. K.. Growth rate inhibition metrics correct for confounders in measuring sensitivity to cancer drugs. Nature Methods. 2016-06-01. 27135972. 4887336.
  28. Mills. C. E.. Subramanian. K.. Hafner. M.. Niepel. M.. Gerosa. L.. Chung. M.. Victor. C.. Gaudio. B.. Yapp. C.. Sorger. P. K.. Multiplexed and reproducible high content screening of live and fixed cells using the Dye Drop method. 2021-09-27. 2021-08-28. 10.1101/2021.08.27.457854. 237356861.
  29. 10.1016/j.chembiol.2019.05.005. 26. 8. 1067–1080.e8. Hafner. M.. Mills. C. E.. Subramanian. K.. Chen. C.. Chung. M.. Boswell. S. A.. Everley. R. A.. Liu. C.. Walmsley. C. S.. Juric. D.. Sorger. P. K.. Multiomics Profiling Establishes the Polypharmacology of FDA-Approved CDK4/6 Inhibitors and the Potential for Differential Clinical Activity. Cell Chemical Biology. 2019-08-15. 31178407. 6936329.
  30. 10.1038/s41592-021-01283-4. 1548-7091. 18. 10. 1169–1180. AlQuraishi. M.. Sorger. P. K.. Differentiable biology: using deep learning for biophysics-based and data-driven modeling of molecular mechanisms. Nature Methods. 2021-10-04. 34608321. 8793939.
  31. 10.1038/s41592-019-0687-1. 17. 2. 175–183. Cunningham. J. M.. Koytiger. G.. Sorger. P. K.. AlQuraishi. M.. Biophysical prediction of protein-peptide interactions and signaling networks using machine learning. Nature Methods. 2020-02-06. 31907444. 7004877.
  32. 10.7554/eLife.31657. 2050-084X. 7. Lin. J.-R.. Izar. B.. Wang. S.. Yapp. C.. Mei. S.. Shah. P. M.. Santagata. S.. Sorger. P. K.. Highly multiplexed immunofluorescence imaging of human tissues and tumors using t-CyCIF and conventional optical microscopes. eLife. 2018-07-11. 29993362. 6075866. free.
  33. 10.1038/s41551-021-00789-8. Rashid. R.. Chen. Y.-A.. Hoffer. J.. Muhlich. J. L.. Lin. J.-R.. Krueger. R.. Pfister. H.. Mitchell. R.. Santagata. S.. Sorger. P. K.. Narrative online guides for the interpretation of digital-pathology images and tissue-atlas data. Nature Biomedical Engineering. 2021-11-08. 6. 5. 515–526. 34750536. 9079188.
  34. Web site: Atlas maker: Q&A with Peter Sorger. Ludwig Cancer Research. 16 December 2021.
  35. Web site: CyCIF - Cyclic Immunofluorescence. 17 December 2021.
  36. 10.1038/s41591-021-01331-8. 27. 6. 985–992. Liu. D.. Lin. J.-R.. Robitschek. E. J.. Kasumova. G. G.. Heyde. A.. Shi. A.. Kraya. A.. Zhang. G.. Moll. T.. Frederick. D. T.. Chen. Y.-A.. Wang. S.. Schapiro. D.. Ho. L.-L.. Bi. K.. Sahu. A.. Mei. S.. Miao. B.. Sharova. T.. Alvarez-Breckenridge. C.. Stocking. J. H.. Kim. T.. Fadden. R.. Lawrence. D.. Hoang. M. P.. Cahill. D. P.. Malehmir. M.. Nowak. M. A.. Brastianos. P. K.. Lian. C. G.. Ruppin. E.. Izar. B.. Herlyn. M.. Van Allen. E. M.. Nathanson. K.. Flaherty. K. T.. Sullivan. R. J.. Kellis. M. Sorger. P. K.. Boland. G. M.. Evolution of delayed resistance to immunotherapy in a melanoma responder. Nature Medicine. 2021-05-03. 33941922. 8474080.
  37. 10.1016/j.cell.2017.11.009. 1097-4172. 171. 7. 1678–1691.e13. Palmer. A. C.. Sorger. P. K.. Combination Cancer Therapy Can Confer Benefit via Patient-to-Patient Variability without Drug Additivity or Synergy. Cell. 2017-12-14. 29245013. 5741091.
  38. 2020–01.31.20019604 . Palmer . A. C . Izar . B. . Sorger . P. K . Combinatorial benefit without synergy in recent clinical trials of immune checkpoint inhibitors . 2020-02-04 . 10.1101/2020.01.31.20019604v2.
  39. 10.1016/j.cct.2020.106126. 98. 106126. Chen. C.. Liu. F.. Ren. Y.. Suttner. L.. Sun. Z.. Shentu. Y.. Schmidt. E. V.. Independent drug action and its statistical implications for development of combination therapies. Contemporary Clinical Trials. 2020-11-01. 32853780. 221359327. 17 December 2021.
  40. Web site: Cancer Trials. CANCERTRIALS.io. 17 December 2021.
  41. Plana. D.. Fell. G.. Alexander. B. M.. Palmer. A. C.. Sorger. P. K.. Cancer patient survival can be accurately parameterized, revealing time-dependent therapeutic effects and doubling the precision of small trials. 2021-05-18. 2021-05-17. 10.1101/2021.05.14.442837. 234785442.
  42. 10.2105/AJPH.2020.305753. 110. 8. 1162–1164. Sinha. M. S.. Bourgeois. F.T.. Sorger. Peter K.. Personal Protective Equipment for COVID-19: Distributed Fabrication and Additive Manufacturing. American Journal of Public Health. 2020-06-18. 32552025. 7349433.
  43. Web site: PanFab News. PanFab. 17 December 2021.
  44. 10.1016/j.medj.2020.06.003. 1. 1. 139–151.e4. Mostaghimi. A.. Antonini. M.-J.. Plana. D.. Anderson. P. D.. Beller. B.. Boyer. E. W.. Fannin. A.. Freake. J.. Oakley. R.. Sinha. M. S.. Smith. L.. Van. C.. Yang. H.. Sorger. P. K.. LeBoeuf. N. R.. Yu. S. H.. Regulatory and Safety Considerations in Deploying a Locally Fabricated, Reusable Face Shield in a Hospital Responding to the COVID-19 Pandemic. Med. 2020-12-18. 32838357. 7304404. 1721.1/128858.
  45. 10.1186/s42490-021-00055-7. 3. 1. 10. McAvoy. M.. Bui. A.-T. N.. Hansen. C.. Plana. D.. Said. J. T.. Yu. Z.. Yang. H.. Freake. J.. Van. C.. Krikorian. D.. Cramer. A.. Smith. L.. Jiang. L.. Lee. K. J.. Li. S. J.. Beller. B.. Huggins. K.. Short. M. P.. Yu. S. H.. Mostaghimi. A.. Sorger. P. K.. LeBoeuf. N. R.. 3D Printed frames to enable reuse and improve the fit of N95 and KN95 respirators. BMC Biomedical Engineering. 2021-06-07. 34099062. 8182357. free.
  46. Kothakonda . A. . Atta . L. . Plana . D. . Ward . F. . Davis . C. . Cramer . A. . Moran . R. . Freake . J. . Tian . E. . Mazor . O. . Gorelik . P. . Van . C. . Hansen . C. . Yang . H. . Sinha . M. S. . Li . J. . Yu . S. H. . LeBoeuf . N. R. . Sorger . P. K. . De novo Powered Air-Purifying Respirator Design and Fabrication for Pandemic Response . 2021-03-29 . 10.1101/2021.03.25.21252076.
  47. 10.1038/s41598-021-81365-7. 11. 1. 2051. Cramer. A. K.. Plana. D.. Yang. H.. Carmack. M. M.. Tian. E.. Sinha. M. S.. Krikorian. D.. Turner. D.. Mo. J.. Li. J.. Gupta. R.. Manning. H.. Bourgeois. F. T.. Yu. S. H.. Sorger. P. K.. LeBoeuf. N. R.. Analysis of SteraMist ionized hydrogen peroxide technology in the sterilization of N95 respirators and other PPE. Scientific Reports. 2021-01-21. 33479334. 7819989.
  48. 10.20944/preprints202009.0577.v1. Antonini. M.-J.. Plana. D.. Srinivasan. S.. Atta. L.. Achanta. A.. Yang. H.. Cramer. A.. Freake. J.. Sinha. M. S.. Yu. S. H.. LeBoeuf. N. R.. Linville-Engler. B.. Sorger. P. K.. A Crisis-Responsive Framework for Medical Device Development during the COVID-19 Pandemic. 2020-12-01. 2020-09-24. 224873745. free.

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